KIF1Bβ increases ROS to mediate apoptosis and reinforces its protein expression through O(2)(−) in a positive feedback mechanism in neuroblastoma

Relapse-prone, poor prognosis neuroblastoma is frequently characterized by deletion of chr1p36 where tumor suppressor gene KIF1Bβ resides. Interestingly, many 1p36-positive patients failed to express KIF1Bβ protein. Since altered cellular redox status has been reported to be involved in cell death and protein modification, we investigated the relationship between reactive oxygen species (ROS) and KIF1Bβ. Here, we showed that wild-type KIF1Bβ protein expression positively correlates with superoxide (O(2) (−)) and total ROS levels in neuroblastoma cells, unlike apoptotic loss-of-function KIF1Bβ mutants. Overexpression of KIF1Bβ apoptotic domain variants increases total ROS and, specifically O(2) (−), whereas knockdown of endogenous KIF1Bβ decreases ROS and O(2) (−). Interestingly, O(2) (−) increases KIF1Bβ protein expression, independent of the proteasomal degradation pathway. Scavenging O(2) (−) or ROS decreases KIF1Bβ protein expression and subsequent apoptosis. Moreover, treatment with investigational redox compound Gliotoxin increases O(2) (−), KIF1Bβ protein expression, apoptosis and colony formation inhibition. Overall, our findings suggest that ROS and O(2) (−) may be important downstream effectors of KIF1Bβ-mediated apoptosis. Subsequently, O(2) (−) produced may increase KIF1Bβ protein expression in a positive feedback mechanism. Therefore, ROS and, specifically O(2) (−), may be critical regulators of KIF1Bβ-mediated apoptosis and its protein expression in neuroblastoma.